Table 1.
Options of Residues in a GLP-1R/GIPR Dual Agonist
| Position | Options | ||
|---|---|---|---|
| For GLP-1 Activity | For GIP Activity | Other Plausible Options | |
| 1 | His↑, Tyr↓ | His↓, Tyr↑ | Phe (may reduce receptor internalization) |
| 2 | Aib↑, Gly↓ | Aib↑, Gly↑, D-Ala↑ | Ala (may be feasible in Fc/albumin fused protein) |
| 3 | - | - | Gln (is used in CY-5) |
| 7 | Thr↑ | Thr↓, Ile↑ (will destroy GLP-1 activity) | - |
| 10 | Tyr↑ | Tyr↑ | - |
| 12 | - | Ile↑ | Leu/Val (is similar to Ile), Lys (is used in exenatide) |
| 13 | Aib↓ (influence may be very little), Tyr↑ | Aib↑ | Gln (is used in exenatide) |
| 14 | Leu↑ | - | - |
| 15 | - | Asp↑ | Glu (is from GLP-1 and similar to Asp) |
| 16 | Lys↓ | Lys↑, Ala↑ | Gln, Glu (is used in exenatide), hGlu |
| 17 | Gln↑ | Ile↑ | - |
| 18 | Ala↑, Arg↑ | Ala↑, Arg↑ | - |
| 19 | - | Gln↑ | - |
| 20 | Lys↑ | - | Arg (is used in exenatide) |
| 21 | Ala↑, Glu↑ | Ala↓, Asp↑ | Leu (is used in exenatide)/Ile/Val |
| 24 | Gln↑ | Gln↑ | - |
Note: ↑ indicates this amino acid would increase activity if is chosen at the position; ↓ indicates decreasing; - means data is lacking.